The lived experience of mental disorders in adolescents: a bottom-up review co-designed, co-conducted and co-written by experts by experience and academics.

We provide here the first bottom-up review of the lived experience of mental disorders in adolescents co-designed, co-conducted and co-written by experts by experience and academics. We screened first-person accounts within and outside the medical field, and discussed them in collaborative workshops involving numerous experts by experience - representing different genders, ethnic and cultural backgrounds, and continents - and their family members and carers. Subsequently, the material was enriched by phenomenologically informed perspectives and shared with all collaborators. The inner subjective experience of adolescents is described for mood disorders, psychotic disorders, attention-deficit/hyperactivity disorder, autism spectrum disorders, anxiety disorders, eating disorders, externalizing disorders, and self-harm behaviors. The recollection of individuals' past histories also indexes the prodromal (often transdiagnostic) features predating the psychiatric diagnosis. The experience of adolescents with mental disorders in the wider society is described with respect to their family, their school and peers, and the social and cultural context. Furthermore, their lived experience of mental health care is described with respect to receiving a diagnosis of mental disorder, accessing mental health support, receiving psychopharmacological treatment, receiving psychotherapy, experiencing peer support and mental health activism, and achieving recovery. These findings can impact clinical practice, research, and the whole society. We hope that this co-designed, co-conducted and co-written journey can help us maintain our commitment to protecting adolescents' fragile mental health, and can help them develop into a healthy, fulfilling and contributing adult life.

Impact of air pollution and climate change on mental health outcomes: an umbrella review of global evidence.

The impact of air pollution and climate change on mental health has recently raised strong concerns. However, a comprehensive overview analyzing the existing evidence while addressing relevant biases is lacking. This umbrella review systematically searched the PubMed/Medline, Scopus and PsycINFO databases (up to June 26, 2023) for any systematic review with meta-analysis investigating the association of air pollution or climate change with mental health outcomes. We used the R metaumbrella package to calculate and stratify the credibility of the evidence according to criteria (i.e., convincing, highly suggestive, suggestive, or weak) that address several biases, complemented by sensitivity analyses. We included 32 systematic reviews with meta-analysis that examined 284 individual studies and 237 associations of exposures to air pollution or climate change hazards and mental health outcomes. Most associations (n=195, 82.3%) involved air pollution, while the rest (n=42, 17.7%) regarded climate change hazards (mostly focusing on temperature: n=35, 14.8%). Mental health outcomes in most associations (n=185, 78.1%) involved mental disorders, followed by suicidal behavior (n=29, 12.4%), access to mental health care services (n=9, 3.7%), mental disorders-related symptomatology (n=8, 3.3%), and multiple categories together (n=6, 2.5%). Twelve associations (5.0%) achieved convincing (class I) or highly suggestive (class II) evidence. Regarding exposures to air pollution, there was convincing (class I) evidence for the association between long-term exposure to solvents and a higher incidence of dementia or cognitive impairment (odds ratio, OR=1.139), and highly suggestive (class II) evidence for the association between long-term exposure to some pollutants and higher risk for cognitive disorders (higher incidence of dementia with high vs. low levels of carbon monoxide, CO: OR=1.587; higher incidence of vascular dementia per 1 µg/m3 increase of nitrogen oxides, NOx: hazard ratio, HR=1.004). There was also highly suggestive (class II) evidence for the association between exposure to airborne particulate matter with diameter ≤10 µm (PM10) during the second trimester of pregnancy and the incidence of post-partum depression (OR=1.023 per 1 µg/m3 increase); and for the association between short-term exposure to sulfur dioxide (SO2) and schizophrenia relapse (risk ratio, RR=1.005 and 1.004 per 1 µg/m3 increase, respectively 5 and 7 days after exposure). Regarding climate change hazards, there was highly suggestive (class II) evidence for the association between short-term exposure to increased temperature and suicide- or mental disorders-related mortality (RR=1.024), suicidal behavior (RR=1.012), and hospital access (i.e., hospitalization or emergency department visits) due to suicidal behavior or mental disorders (RR=1.011) or mental disorders only (RR=1.009) (RR values per 1°C increase). There was also highly suggestive (class II) evidence for the association between short-term exposure to increased apparent temperature (i.e., the temperature equivalent perceived by humans) and suicidal behavior (RR=1.01 per 1°C increase). Finally, there was highly suggestive (class II) evidence for the association between the temporal proximity of cyclone exposure and severity of symptoms of post-traumatic stress disorder (r=0.275). Although most of the above associations were small in magnitude, they extend to the entire world population, and are therefore likely to have a substantial impact. This umbrella review classifies and quantifies for the first time the global negative impacts that air pollution and climate change can exert on mental health, identifying evidence-based targets that can inform future research and population health actions.

Sexually transmitted infections, sexual life and risk behaviours of people living with schizophrenia: systematic review and meta-analysis.

BACKGROUND: Sexually transmitted infections (STIs), along with sexual health and behaviour, have received little attention in schizophrenia patients. AIMS: To systematically review and meta-analytically characterise the prevalence of STIs and sexual risk behaviours among schizophrenia patients. METHOD: Web of Science, PubMed, BIOSIS, KCI-Korean Journal Database, MEDLINE, Russian Science Citation Index, SciELO and Cochrane Central Register were systematically searched from inception to 6 July 2023. Studies reporting on the prevalence or odds ratio of any STI or any outcome related to sexual risk behaviours among schizophrenia samples were included. PRISMA/MOOSE-compliant (CRD42023443602) random-effects meta-analyses were used for the selected outcomes. Q-statistics, I2 index, sensitivity analyses and meta-regressions were used. Study quality and publication bias were assessed. RESULTS: Forty-eight studies (N = 2 459 456) reporting on STI prevalence (including 15 allowing for calculation of an odds ratio) and 33 studies (N = 4255) reporting on sexual risk behaviours were included. Schizophrenia samples showed a high prevalence of STIs and higher risks of HIV (odds ratio = 2.11; 95% CI 1.23-3.63), hepatitis C virus (HCV, odds ratio = 4.54; 95% CI 2.15-961) and hepatitis B virus (HBV; odds ratio = 2.42; 95% CI 1.95-3.01) infections than healthy controls. HIV prevalence was higher in Africa compared with other continents and in in-patient (rather than out-patient) settings. Finally, 37.7% (95% CI 31.5-44.4%) of patients were sexually active; 35.0% (95% CI 6.6-59.3%) reported consistent condom use, and 55.3% (95% CI 25.0-82.4%) maintained unprotected sexual relationships. CONCLUSIONS: Schizophrenia patients have high prevalence of STIs, with several-fold increased risks of HIV, HBV and HCV infection compared with the general population. Sexual health must be considered as an integral component of care.

Exploring causal mechanisms of psychosis risk.

Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.

A transdiagnostic prodrome for severe mental disorders: an electronic health record study.

Effective prevention of severe mental disorders (SMD), including non-psychotic unipolar mood disorders (UMD), non-psychotic bipolar mood disorders (BMD), and psychotic disorders (PSY), rely on accurate knowledge of the duration, first presentation, time course and transdiagnosticity of their prodromal stages. Here we present a retrospective, real-world, cohort study using electronic health records, adhering to RECORD guidelines. Natural language processing algorithms were used to extract monthly occurrences of 65 prodromal features (symptoms and substance use), grouped into eight prodromal clusters. The duration, first presentation, and transdiagnosticity of the prodrome were compared between SMD groups with one-way ANOVA, Cohen's f and d. The time course (mean occurrences) of prodromal clusters was compared between SMD groups with linear mixed-effects models. 26,975 individuals diagnosed with ICD-10 SMD were followed up for up to 12 years (UMD = 13,422; BMD = 2506; PSY = 11,047; median[IQR] age 39.8[23.7] years; 55% female; 52% white). The duration of the UMD prodrome (18[36] months) was shorter than BMD (26[35], d = 0.21) and PSY (24[38], d = 0.18). Most individuals presented with multiple first prodromal clusters, with the most common being non-specific ('other'; 88% UMD, 85% BMD, 78% PSY). The only first prodromal cluster that showed a medium-sized difference between the three SMD groups was positive symptoms (f = 0.30). Time course analysis showed an increase in prodromal cluster occurrences approaching SMD onset. Feature occurrence across the prodromal period showed small/negligible differences between SMD groups, suggesting that most features are transdiagnostic, except for positive symptoms (e.g. paranoia, f = 0.40). Taken together, our findings show minimal differences in the duration and first presentation of the SMD prodromes as recorded in secondary mental health care. All the prodromal clusters intensified as individuals approached SMD onset, and all the prodromal features other than positive symptoms are transdiagnostic. These results support proposals to develop transdiagnostic preventive services for affective and psychotic disorders detected in secondary mental healthcare.

Why we need to pursue both universal and targeted prevention to reduce the incidence of affective and psychotic disorders: Systematic review and meta-analysis.

The effectiveness of universal preventive approaches in reducing the incidence of affective/psychotic disorders is unclear. We therefore aimed to synthesise the available evidence from randomised controlled trials. For studies reporting change in prevalence, we simulated all possible scenarios for the proportion of individuals with the disorder at baseline and at follow-up to exclude them. We then combined these data with studies directly measuring incidence and conducted random effects meta-analysis with relative risk (RR) to estimate the incidence in the intervention group compared to the control group. Eighteen studies (k=21 samples) were included investigating the universal prevention of depression in 66,625 individuals. No studies were available investigating universal prevention on the incidence of bipolar/psychotic disorders. 63 % of simulated scenarios showed a significant preventive effect on reducing the incidence of depression (k=9 - 19, RR=0.75-0.94, 95 %CIs=0.55-0.87,0.93-1.15, p=0.007-0.246) but did not survive sensitivity analyses. There is some limited evidence for the effectiveness of universal interventions for reducing the incidence of depression but not for bipolar/psychotic disorders.

Effect of long-acting antipsychotic treatment on psychiatric hospitalization rate in early psychosis patients: a naturalistic study.

Background: The effectiveness of long-acting injectable (LAI) antipsychotics in preventing relapses of first-episode psychosis is currently debated. Objectives: The study aimed to investigate the number of psychiatric hospitalizations comparing the LAI cohort versus the oral cohort during different phases of the illness, pre-LAI treatment, during LAI treatment, and after LAI treatment. Design: A naturalistic study was conducted on two independent cohorts of early psychosis patients receiving treatment from a specific early intervention service. The first cohort comprised 228 patients who received LAIs, while the second cohort comprised 667 patients who had never received LAIs. Methods: This study was designed as a longitudinal observational study conducted within a naturalistic clinical setting in two cohorts of early psychosis patients. Repeated series ANCOVA (ANCOVA-r) was used to study the number of hospitalizations in the different study periods (T1 = from the date of the first psychiatric record to the beginning of the mirror period; T2 = the mirror period; T3 = from the LAI implementation to the LAI discontinuation; and T4 = from the LAI discontinuation to the end). In all cases, discontinuation of LAI involved the return to oral treatment. In all, 35 patients had not T4 as they were still on LAI treatment at the time of database closing (September 2020), and their data were not included in the analysis of the effect of the LAI discontinuation. Results: The patients in the LAI cohort were younger, more frequently males, presented more schizophrenia diagnoses, and had a higher number of hospitalizations (2.50 ± 2.61 versus 1.19 ± 1.69; p < 0.001) than the oral cohort. The number of hospitalizations at the end of the follow-up was higher in the LAI cohort [0.20 (standard deviation (SD)) = 0.79] versus 0.45 [SD = 0.45 (SD = 1.13); F(23.90), p < 0.001]. However, after the introduction of LAIs, the differences in hospitalization rates between the two cohorts became less pronounced. Once LAI treatment was ceased, the hospitalization rate increased again. Conclusion: In our study, early psychosis patients receiving LAIs experienced a greater decrease in hospitalizations after introducing the LAI treatment than those treated solely with oral medication. These findings support using LAIs as a viable strategy for preventing rehospitalization and improving the overall course of treatment for individuals with early psychosis.

Enhancing Psychotherapy Outcomes by Encouraging Patients to Regularly Self-Monitor, Reflect on, and Share Their Affective Responses Toward Their Therapist: Protocol for a Randomized Controlled Trial.

BACKGROUND: The quality of the therapeutic relationship is pivotal in determining psychotherapy outcomes. However, facilitating patients' self-awareness, reflection on, and sharing of their affective responses toward their therapist remains underexplored as a potential tool for enhancing this relationship and subsequent treatment outcomes. OBJECTIVE: The primary objective of this study is to examine whether and how the patients' regular self-monitoring and self-reflection (fostered by the systematic compilation of a brief postsession battery) on their affective reactions toward the psychotherapist impact the quality of the therapeutic relationship and treatment outcomes in individual psychotherapy. Secondary objectives are to (1) explore whether and how the characteristics of the patient, the therapist, and the process moderate the effect of regular self-monitoring on the therapeutic relationship and outcomes; (2) examine the relationships between the affective response of the patient, the alliance, and the result of the therapy session outcome; and (3) explore how the affective responses of the patient unfold or change throughout the course of the therapy. METHODS: We conducted a 1:1 randomized controlled trial of adults in individual psychotherapy versus individual psychotherapy plus self-monitoring. Participants will be enrolled through the web-based recruitment platforms "ResearchMatch" and "Research for Me," and data will be collected through web-based surveys. Participants in the control group will receive only their regular individual psychotherapy (treatment as usual) and will not complete postsession questionnaires. Participants in the intervention group will continue their regular individual psychotherapy sessions and complete the "in-Session Patient Affective Reactions Questionnaire" and the "Rift In-Session Questionnaire" following each therapy session in the 10 weeks of the trial. Additionally, after completion of the postsession battery, they will receive general written feedback encouraging them to discuss their feelings and reflections with their therapist. Participants in both groups will complete a comprehensive psychological assessment at baseline, midtrial (week 5), and end-of-trial (week 10). The primary outcome measure of the trial is the "Clinical Outcomes in Routine Evaluation-Outcome Measure," while the secondary outcomes are the "Real Relationship Inventory-Client-Short Form," the "Working Alliance Inventory-Short Revised," and the number of scheduled therapy sessions that the patient has missed or canceled. RESULTS: The trial was approved by the institutional review board of the University of North Carolina at Chapel Hill. Recruitment started in September 2023. A total of 475 individuals completed the baseline assessment. Data collection was completed in February 2024. The results are expected to be published in the autumn of 2024. CONCLUSIONS: This study could reveal key information on how regular self-monitoring and introspection can influence both the therapeutic relationship and treatment outcomes. Findings have the potential to shape interventions, enhance the efficacy of psychotherapeutic sessions, and possibly offer a cost-effective strategy for improving patients' well-being. TRIAL REGISTRATION: ClinicalTrials.gov NCT06038747; https://classic.clinicaltrials.gov/ct2/show/NCT06038747. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55369.

Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis.

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, pFDR < 0.001) and across its subfields (all pFDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all pFDR < 0.001) was significantly reduced (t(69) = -5.1, pFDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, pFDR = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

Effects of Benzodiazepine Exposure on Real-World Clinical Outcomes in Individuals at Clinical High Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences real-world clinical outcomes in individuals at clinical high risk for psychosis (CHR-P) is unknown. STUDY DESIGN: This observational cohort study used electronic health record data from CHR-P individuals to investigate whether BDZ exposure (including hypnotics, eg, zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample. STUDY RESULTS: 567 CHR-P individuals (306 male, mean[±SD] age = 22.3[±4.9] years) were included after data cleaning. The BDZ-exposed (n = 105) and BDZ-unexposed (n = 462) groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR = 1.61; 95% CI: 1.03-2.52; P = .037), psychiatric hospital admission (HR = 1.93; 95% CI: 1.13-3.29; P = .017), home visit (HR = 1.64; 95% CI: 1.18-2.28; P = .004), and Accident and Emergency department attendance (HR = 1.88; 95% CI: 1.31-2.72; P < .001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P > .05). In an analysis restricted to antipsychotic-naïve individuals, BDZ exposure reduced the risk of transition to psychosis numerically, although this was not statistically significant (HR = 0.59; 95% CI: 0.32-1.08; P = .089). CONCLUSIONS: BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity.

Development and validation of an 8-item version of the Real Relationship Inventory-Client form.

OBJECTIVE: To develop and validate a very brief version of the 24-item Real Relationship Inventory-Client (RRI-C) form. METHOD: Two independent samples of individual psychotherapy patients (Nsample1 = 700, Nsample2 = 434) completed the RRI-C along with other measures. Psychometric scale shortening involved exploratory factor analysis, item response theory analysis, confirmatory factor analysis (CFA), and multigroup CFA. Reliability and convergent and discriminant validity of the scale and subscales were also assessed. RESULTS: The 8-item RRI-C (RRI-C-SF) preserves the two-factor structure: Genuineness (k = 4, α = .86) and Realism (k = 4, α = .87), which were correlated at r = .74. CFA provided the following fit indices for the bifactor model: X2/df = 2.16, CFI = .99, TLI = .96, RMSEA = .07, and SRMR = .03. Multigroup CFA showed that the RRI-C-SF was invariant across in-person and remote session formats. The RRI-C-SF demonstrated high reliability (α = .91); high correlation with the full-length scale (r = .96); and excellent convergent and discriminant validity with measures of other elements of the therapeutic relationship, personality characteristics, current mental health state, and demographic-clinical variables. Clinical change benchmarks were calculated to serve as valuable tools for both research and clinical practice. CONCLUSION: The RRI-C-SF is a reliable measure that can be used for both research and clinical purposes. It enables a nuanced assessment of the genuineness and the realism dimensions of the real relationship.

On the interplay between state-dependent reconfigurations of global signal correlation and BOLD fluctuations: An fMRI study.

BACKGROUND: The dynamics of global, state-dependent reconfigurations in brain connectivity are yet unclear. We aimed at assessing reconfigurations of the global signal correlation coefficient (GSCORR), a measure of the connectivity between each voxel timeseries and the global signal, from resting-state to a stop-signal task. The secondary aim was to assess the relationship between GSCORR and blood-oxygen-level-dependent (BOLD) activations or deactivation across three different trial-conditions (GO, STOP-correct, and STOP-incorrect). METHODS: As primary analysis we computed whole-brain, voxel-wise GSCORR during resting-state (GSCORR-rest) and stop-signal task (GSCORR-task) in 107 healthy subjects aged 21-50, deriving GSCORR-shift as GSCORR-task minus GSCORR-rest. GSCORR-tr and trGSCORR-shift were also computed on the task residual time series to quantify the impact of the task-related activity during the trials. To test the secondary aim, brain regions were firstly divided in one cluster showing significant task-related activation and one showing significant deactivation across the three trial conditions. Then, correlations between GSCORR-rest/task/shift and activation/deactivation in the two clusters were computed. As sensitivity analysis, GSCORR-shift was computed on the same sample after performing a global signal regression and GSCORR-rest/task/shift were correlated with the task performance. RESULTS: Sensory and temporo-parietal regions exhibited a negative GSCORR-shift. Conversely, associative regions (ie. left lingual gyrus, bilateral dorsal posterior cingulate gyrus, cerebellum areas, thalamus, posterolateral parietal cortex) displayed a positive GSCORR-shift (FDR-corrected p < 0.05). GSCORR-shift showed similar patterns to trGSCORR-shift (magnitude increased) and after global signal regression (magnitude decreased). Concerning BOLD changes, Brodmann area 6 and inferior parietal lobule showed activation, while posterior parietal lobule, cuneus, precuneus, middle frontal gyrus showed deactivation (FDR-corrected p < 0.05). No correlations were found between GSCORR-rest/task/shift and beta-coefficients in the activation cluster, although negative correlations were observed between GSCORR-task and GO/STOP-correct deactivation (Pearson rho=-0.299/-0.273; Bonferroni-p < 0.05). Weak associations between GSCORR and task performance were observed (uncorrected p < 0.05). CONCLUSION: GSCORR state-dependent reconfiguration indicates a reallocation of functional resources to associative areas during stop-signal task. GSCORR, activation and deactivation may represent distinct proxies of brain states with specific neurofunctional relevance.

Physical Health and Transition to Psychosis in People at Clinical High Risk.

BACKGROUND: The clinical high risk for psychosis (CHR-P) construct represents an opportunity for prevention and early intervention in young adults, but the relationship between risk for psychosis and physical health in these patients remains unclear. METHODS: We conducted a RECORD-compliant clinical register-based cohort study, selecting the long-term cumulative risk of developing a persistent psychotic disorder as the primary outcome. We investigated associations between primary outcome and physical health data with Electronic Health Records at the South London and Maudsley (SLaM) NHS Trust, UK (January 2013-October 2020). We performed survival analyses using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. RESULTS: The database included 137 CHR-P subjects; 21 CHR-P developed psychosis during follow-up, and the cumulative incidence of psychosis risk was 4.9% at 1 year and 56.3% at 7 years. Log-rank tests suggested that psychosis risk might change between different levels of nicotine and alcohol dependence. Kaplan-Meier curve analyses indicated that non-hazardous drinkers may have a lower psychosis risk than non-drinkers. In the Cox proportional hazard model, nicotine dependence presented a hazard ratio of 1.34 (95% CI: 1.1-1.64) (p = 0.01), indicating a 34% increase in psychosis risk for every additional point on the Fagerström Test for Nicotine Dependence. CONCLUSIONS: Our findings suggest that a comprehensive assessment of tobacco and alcohol use, diet, and physical activity in CHR-P subjects is key to understanding how physical health contributes to psychosis risk.

Duration of Untreated Psychosis and Outcomes in First-Episode Psychosis: Systematic Review and Meta-analysis of Early Detection and Intervention Strategies.

BACKGROUND: The role of duration of untreated psychosis (DUP) as an early detection and intervention target to improve outcomes for individuals with first-episode psychosis is unknown. STUDY DESIGN: PRISMA/MOOSE-compliant systematic review to identify studies until February 1, 2023, with an intervention and a control group, reporting DUP in both groups. Random effects meta-analysis to evaluate (1) differences in DUP in early detection/intervention services vs the control group, (2) the efficacy of early detection strategies regarding eight real-world outcomes at baseline (service entry), and (3) the efficacy of early intervention strategies on ten real-world outcomes at follow-up. We conducted quality assessment, heterogeneity, publication bias, and meta-regression analyses (PROSPERO: CRD42020163640). STUDY RESULTS: From 6229 citations, 33 intervention studies were retrieved. The intervention group achieved a small DUP reduction (Hedges' g = 0.168, 95% CI = 0.055-0.283) vs the control group. The early detection group had better functioning levels (g = 0.281, 95% CI = 0.073-0.488) at baseline. Both groups did not differ regarding total psychopathology, admission rates, quality of life, positive/negative/depressive symptoms, and employment rates (P > .05). Early interventions improved quality of life (g = 0.600, 95% CI = 0.408-0.791), employment rates (g = 0.427, 95% CI = 0.135-0.718), negative symptoms (g = 0.417, 95% CI = 0.153-0.682), relapse rates (g = 0.364, 95% CI = 0.117-0.612), admissions rates (g = 0.335, 95% CI = 0.198-0.468), total psychopathology (g = 0.298, 95% CI = 0.014-0.582), depressive symptoms (g = 0.268, 95% CI = 0.008-0.528), and functioning (g = 0.180, 95% CI = 0.065-0.295) at follow-up but not positive symptoms or remission (P > .05). CONCLUSIONS: Comparing interventions targeting DUP and control groups, the impact of early detection strategies on DUP and other correlates is limited. However, the impact of early intervention was significant regarding relevant outcomes, underscoring the importance of supporting early intervention services worldwide.

Development and preliminary validation of the Clinician Affective REsponse (CARE) scale.

The present study reports on the development and validation of the clinician affective response (CARE) scale. The CARE scale was designed as a self-report measure of therapists' patterns of thoughts, feelings, and behaviors toward the patient during an individual psychotherapy session. An initial pool of 116 items was generated, and its quality was evaluated by subject matter experts. Validation data were gathered from licensed psychotherapists (n=554). We used exploratory factor analysis and item response theory-graded response modeling to select items, confirmatory factor analysis to test how well the factor structure fit the data, and k-fold cross-validation to ascertain the robustness of the model. Criterion validity was evaluated by correlating the scores of the scale with the characteristics of therapists, patients, and treatment. The selected model consists of 15 items and a 3-factor structure, which showed excellent model fit, good internal consistency, and evidence of criterion validity. The CARE scale, short and quick to complete, enables therapists to reflect on and recognize their inner experiences and quantify these experiences in ways conducive to statistical analysis and research. Furthermore, the monitoring of these affective reactions toward their patients can guide therapeutic interventions and inform clinical supervisors.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Using Electronic Health Records to Facilitate Precision Psychiatry.

The use of clinical prediction models to produce individualized risk estimates can facilitate the implementation of precision psychiatry. As a source of data from large, clinically representative patient samples, electronic health records (EHRs) provide a platform to develop and validate clinical prediction models, as well as potentially implement them in routine clinical care. The current review describes promising use cases for the application of precision psychiatry to EHR data and considers their performance in terms of discrimination (ability to separate individuals with and without the outcome) and calibration (extent to which predicted risk estimates correspond to observed outcomes), as well as their potential clinical utility (weighing benefits and costs associated with the model compared to different approaches across different assumptions of the number needed to test). We review 4 externally validated clinical prediction models designed to predict psychosis onset, psychotic relapse, cardiometabolic morbidity, and suicide risk. We then discuss the prospects for clinically implementing these models and the potential added value of integrating data from evidence syntheses, standardized psychometric assessments, and biological data into EHRs. Clinical prediction models can utilize routinely collected EHR data in an innovative way, representing a unique opportunity to inform real-world clinical decision making. Combining data from other sources (e.g., meta-analyses) or enhancing EHR data with information from research studies (clinical and biomarker data) may enhance our abilities to improve the performance of clinical prediction models.

Regional differences in mortality risk and in attenuating or aggravating factors in schizophrenia: A systematic review and meta-analysis.

People with schizophrenia die prematurely, yet regional differences are unclear. PRISMA 2020-compliant systematic review/random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) versus any control group, and moderators, in people with ICD/DSM-defined schizophrenia, comparing countries and continents. We conducted subgroup, meta-regression analyses, and quality assessment. The primary outcome was all-cause mortality. Secondary outcomes were suicide-, /natural-cause- and other-cause-related mortality. We included 135 studies from Europe (n = 70), North-America (n = 29), Asia (n = 33), Oceania (n = 2), Africa (n = 1). In incident plus prevalent schizophrenia, differences across continents emerged for all-cause mortality (highest in Africa, RR=5.98, 95 %C.I.=4.09-8.74, k = 1, lowest in North-America, RR=2.14, 95 %C.I.=1.92-2.38, k = 16), suicide (highest in Oceania, RR=13.5, 95 %C.I.=10.08-18.07, k = 1, lowest in North-America, RR=4.4, 95 %C.I.=4.07-4.76, k = 6), but not for natural-cause mortality. Europe had the largest association between antipsychotics and lower all-cause mortality/suicide (Asia had the smallest or no significant association, respectively), without differences for natural-cause mortality. Higher country socio-demographic index significantly moderated larger suicide-related and smaller natural-cause-related mortality risk in incident schizophrenia, with reversed associations in prevalent schizophrenia. Antipsychotics had a larger/smaller protective association in incident/prevalent schizophrenia regarding all-cause mortality, and smaller protective association for suicide-related mortality in prevalent schizophrenia. Additional regional differences emerged in incident schizophrenia, across countries, and secondary outcomes. Significant regional differences emerged for all-cause, cause-specific and suicide-related mortality. Natural-cause death was homogeneously increased globally. Moderators differed across countries. Global initiatives are needed to improve physical health in people with schizophrenia, local studies to identify actionable moderators.

Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

Efficacy and effectiveness of antipsychotics in schizophrenia: network meta-analyses combining evidence from randomised controlled trials and real-world data.

BACKGROUND: There is debate about the generalisability of results from randomised clinical trials (RCTs) to real-world settings. Studying outcomes of treatments for schizophrenia can shed light on this issue and inform treatment guidelines. We therefore compared the efficacy and effectiveness of antipsychotics for relapse prevention in schizophrenia and estimated overall treatment effects using all available RCT and real-world evidence. METHODS: We conducted network meta-analyses using individual participant data from Swedish and Finnish national registries and aggregate data from RCTs. The target population was adults (age >18 and <65 years) with schizophrenia and schizoaffective disorder with stabilised symptoms. We analysed each registry separately to obtain hazard ratios (HRs) and 95% CIs for relapse within 6 months post-antipsychotic initiation as our main outcome. Interventions studied were antipsychotics, no antipsychotic use, and placebo. We compared HRs versus a reference drug (oral haloperidol) between registries, and between registry individuals who would be eligible and ineligible for RCTs, using the ratio of HRs. We synthesised evidence using network meta-analysis and compared results from our network meta-analysis of real-world data with our network meta-analysis of RCT data, including oral versus long-acting injectable (LAI) formulations. Finally, we conducted a joint real-world and RCT network meta-analysis. FINDINGS: We included 90 469 individuals from the Swedish and Finnish registries (mean age 45·9 [SD 14·6] years; 43 025 [47·5%] women and 47 467 [52·5%] men, ethnicity data unavailable) and 10 091 individuals from 30 RCTs (mean age 39·6 years [SD 11·7]; 3724 [36·9%] women and 6367 [63·1%] men, 6022 White [59·7%]). We found good agreement in effectiveness of antipsychotics between Swedish and Finnish registries (HR ratio 0·97, 95% CI 0·88-1·08). Drug effectiveness versus no antipsychotic was larger in RCT-eligible than RCT-ineligible individuals (HR ratio 1·40 [1·24-1·59]). Efficacy versus placebo in RCTs was larger than effectiveness versus no antipsychotic in real-world (HR ratio 2·58 [2·02-3·30]). We found no evidence of differences between effectiveness and efficacy for between-drug comparisons (HR ratio vs oral haloperidol 1·17 [0·83-1·65], where HR ratio >1 means superior effectiveness in real-world to RCTs), except for LAI versus oral comparisons (HR ratio 0·73 [0·53-0·99], indicating superior effectiveness in real-world data relative to RCTs). The real-world network meta-analysis showed clozapine was most effective, followed by olanzapine LAI. The RCT network meta-analysis exhibited heterogeneity and inconsistency. The joint real-world and RCT network meta-analysis identified olanzapine as the most efficacious antipsychotic amongst those present in both RCTs and the real world registries. INTERPRETATION: LAI antipsychotics perform slightly better in the real world than according to RCTs. Otherwise, RCT evidence was in line with real-world evidence for most between-drug comparisons, but RCTs might overestimate effectiveness of antipsychotics observed in routine care settings. Our results further the understanding of the generalisability of RCT findings to clinical practice and can inform preferential prescribing guidelines. FUNDING: None.